1. Field of the Invention
The novel chemicals of the present invention include potassium 2.beta.-chloromethyl-2.alpha.-methylpenam-3.alpha.-carboxylate sulfone which is useful as an inhibitor of .beta.-lactamases.
2. Description of the Prior Art
The presumed association between the resistance shown by .beta.-lactam antibiotics to certain bacteria and the ability of those bacteria to produce .beta.-lactamases has led to an intensive search for .beta.-lactamase inhibitors. Clavulanic acid is an example of such a compound presently under intensive study. Another .beta.-lactamase inhibitor has in its acid form the structure ##STR1## and is disclosed in European Patent Application 2927 published July 11, 1979.
The compound having the structure ##STR2## is disclosed in U.S. Pat. Nos. 4,036,847, 4,009,159, 3,993,646, 3,989,685 and 3,954,732.
For a corresponding sulfoxide having the 6-amino group acylated and, for example, the structure ##STR3## see Tetrahedron Letters, 38:3303-3310 (1975) and Kukolja et al., J. Org. Chem., 41, 2276-2279 (1976).
1,1-Dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof have been disclosed in U.S. Pat. No. 3,197,466 and 3,536,698, and in an article by Guddal et al., Tetrahedron Letters, No. 9, 381 (1962). Harrison et al., in the Journal of the Chemical Society (London), Perkin I, 1772 (1976), have disclosed a variety of penicillin 1,1-dioxides, including methyl phthalimidopenicillanate 1,1-dioxide and methyl 6,6-dibromopenicillanate 1,1-dioxide. U.S. Pat. No. 3,544,581 discloses 6-aminopenicillanic acid 1-oxide.
For a brief review of esters of penicillins, see U.S. Pat. No. 3,996,236. Recent U.S. Pat. Nos. on esters of ampicillin and similar derivatives include 4,217,274, 4,081,546, 4,046,759, 4,036,829, 3,963,704, 3,954,735, 3,951,954, 3,941,774, 3,939,180, 3,931,150, 3,873,521, 3,860,579 and 3,697,507.
Recent U.S. Pat. Nos. on compounds (e.g. esters) or mixtures containing two like or unlike .beta.-lactam derivatives include 4,181,659, 3,928,595, 3,869,449 and 3,867,538.
U.S. Pat. No. 4,155,912 describes 2-penem-3-carboxylic acid compounds having the formula ##STR4## and esters and salts, and see also Farmdoc Abstracts 82090A, 10336B and 44337B.
The compound (under the number CP-45899) having the structure ##STR5## is an irreversibly acting .beta.-lactamase inhibitor with excellent solution stability. It has weak antibacterial activity and potentiates the in vitro and in vivo activities of ampicillin versus .beta.-lactamase-producing strains [A. R. English et al., Antimicrobial Agents and Chemotherapy, 14, 414-419 (1978), Aswapokee et al., J. Antibiotics 31(12), 1238-1244 (Dec. 1978) and Derwent's Farmdoc Abstracts 89627A and 73866B].
Cignarella and associates [J. Org. Chem. 27, 2668 (1962)] reported the first deamination of 6-aminopenicillanic acid (6-APA) (1). When treated with sodium nitrite and hydrochloric acid, 6-APA was converted to 6-chloropenicillanic acid (96), isolated as the dibenzylethylenediamine salt. Substitution of hydrobromic acid in the reaction gave the 6-bromo derivative (97). Both deaminated products were devoid of microbiological activity against M. pyogenes aureus 209P. ##STR6##
Evrard and co-workers [Nature, 201, 1124 (1964)] prepared the methyl esters of (96) and (97) and showed that (97) could be hydrogenated to penicillanic acid (98). Their study emphasized the value of gas chromatography in the separation of penicillanates including methyl penicillanate (99). ##STR7##
Compound 98 above is also described in U.K. Pat. No. 1,072,108 (1967).
6.beta.-Bromopenicillanic acid is claimed in U.S. Pat. No. 4,180,506 and described as potentiating the in vitro activity of benzylpenicillin and ampicillin against certain bacteria.
According to U.S. Pat. Nos. 4,203,992 and 4,203,993 (2S,5R,6S)-6.beta.-Bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept ane-2-carboxylic acid, S,S-dioxide, physiologically acceptable salts thereof and readily hydrolyzable ester thereof inhibit the action of the .beta.-lactamase enzyme RTEM.
EPO 13,617 states that its invention relates to a process for the preparation of certain penicillin derivatives which are useful as .beta.-lactamase inhibitors. The compounds which may be prepared by the process of this invention have formula (1), or a pharmaceutically acceptable salt or ester thereof: ##STR8## wherein R represents hydrogen, halogen, C.sub.1-6 alkylthio, C.sub.1-6 alkyl or alkyl substituted with phenyl, carboxy, C.sub.1-6 alkoxycarbonyl, hydroxy or C.sub.1-6 alkylthio, and n is zero, 1 or 2. In addition certain of the compounds produced by the process of the invention are novel compounds. Claim 1 therein reads as follows:
1. A compound of the formula (II): ##STR9## or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof wherein X is a bromine or chlorine atom, and n is zero, 1 or 2, when substantially free from the corresponding 6.alpha.-substituted compound.
The compound (under the number CP-45,899) having the structure ##STR10## is an irreversibly acting .beta.-lactamase inhibitor with excellent solution stability. It has weak antibacterial activity and potentiates the in vitro and in vivo activities of ampicillin versus .beta.-lactamase-producing strains [see Derwent's Farmdoc Abstracts 89627A and 73866B].
It is disclosed by B. Baltzer et al., Mutual Pro-Drugs of .beta.-Lactam Antibiotics and .beta.-Lactamase Inhibitors, J. Antibiotics, 33(10), 1183-1192 (1980) that the principle of combining .beta.-lactam antibiotic with a .beta.-lactamase inhibitor in a single molecule functioning as pro-drug for the two active components is illustrated by the linked esters 3 and 4 in which ampicillin and mecillinam, respectively, are combined with the .beta.-lactamase inhibitor penicillanic acid sulfone. It is shown that in man these esters are excellently absorbed from the gastro-intestinal tract and after absorption hydrolyzed with simultaneous liberation of the active components. As a result high blood and tissue levels of antibiotic and .beta.-lactamase inhibitor in a balanced ratio are attained. The advantages of "mutual pro-drugs" over simple combinations are discussed.
Esters 3 and 4 referred to therein have the structures ##STR11##
The following publications were discussed in the Baltzer et al. publication:
(1) Von Daehne, W.; E. Frederiksen, E. Gundersen, F. Lund, P. Morch, H. J. Petersen, K. Roholt, L. Tybring & W. O. Godtfredsen: Acyloxymethyl esters of ampicillin. J. Med. Chem. 13: 607-612, 1970
(2) Binderup, E.; W. P. Godtfredsen & K. Roholt: Orally active cephaloglycin esters. J. Antibiotics 24: 767-773, 1971
(3) Wheeler, W. J.; W. E. Wright, V. D. Line & J. A. Frogge: Orally active esters of cephalosporin antibiotics. Synthesis and biological properties of 7-(D-2-amino-2-phenylacetamido)-3-[5-methyl-(1,3,4-thiadiazol-2-yl)thio methyl]-3-cephem-4-carboxylic acid. J. Med. Chem. 20: 1159-1164, 1977
(4) Wheeler, W. J.; D. A. Preston, W. E. Wright, G. W. Huffman, H. E. Osborne & D. P. Howard: Orally active esters of cephalosporin antibiotics. 3. Synthesis and biological properties of aminoacyloxymethyl esters of 7-[D-(-)-mandelamino]-3-[[(1-methyl-1Htetrazol-5-yl)thio]methyl]-3-cephem- 4-carboxylic acid. J. Med. Chem. 22: 657-661, 1979
(5) Wright, W. E.; W. J. Wheeler, V. D. Line, J. A. Frogge & D. R. Finley: Orally active esters of cephalosporin antibiotics. II. Synthesis and biological properties of the acetoxymethyl ester of cefamandole. J. Antibiotics 32: 1155-1160, 1979
(6) Roholt, K.: Pharmacokinetic studies with mecillinam and pivmecillinam. J. Antimicrob. Chemother. 3 (Suppl. B): 71-81 1977
(7) Foulds, G.; W. E. Barth, J. R. Bianchine, A. R. English, D. Girard, S. L. Hayes, M. M. O'Brien & P. Somani: Pharmacokinetics of CP-45,899 and pro-drug CP-47,904 in animals and humans. Current Chemother, & Infect. Disease 1980: 353, 1980
(8) Aswapokee, N. & H. C. Neu: A sulfone .beta.-lactam compound which acts as a .beta.-lactamase inhibitor. J. Antibiotics 31: 1238-1244, 1978
(9) Engberg-Pedersen, H: Empirical equation for pharmacokinetic analysis of drug serum levels after oral application. Antimicr. Agents & Chemoth. 6: 554-562, 1974
(10) Jordan, M. C.; J. B. De Maine & W. M. M. Kirby: Clinical pharmacology of pivampicillin as compared with ampicillin. Antimicr. Agents & Chemoth.-1970: 438-441, 1971
(11) Godtfredsen, W. O.: U.S. Pat. No. 3,869,449, 1975
(12) Christensen, B. G. & W. J. Leanza: U.S. Pat. No. 3,931,150, 1976
(13) Evrard, E.; M. Claesen & H. Vanderhaeghe: Gas chromatography of penicillin and penicillanic acid esters. Nature 201: 1124-1125, 1964
(14) English, A. R.; J. A. Retsema, A. E. Girard, J. E. Lynch & W. E. Barth: GP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of betalactam: Initial bacteriological characterization. Antimicro. Agents & Chemoth. 14: 414-419, 1978
It is stated in GB 2044255 published Oct. 15, 1980 that the invention therein relates to hitherto unknown compounds of the general formula 1: ##STR12## in which R.sub.1 stands for a phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or a 3-thienyl group; R.sub.2 represents a primary amino or a carboxy group; R.sub.3 is a hydrogen atom, or a lower alkyl, aryl or aralkyl radical, and A stands for a radical of a .beta.-lactamase inhibitor containing a .beta.-lactam ring as well as a carboxy group, A being connected via the carboxy group.
The new compounds are useful in the treatment of bacterial infections and are in particular strongly active against .beta.-lactamase producing bacteria. See also Farmdoc abstracts 60773C and 60776C.